DESCRIPTION: The primary hypothesis in this proposal is that intraocular IOP is regulated by two intrinsic mechanisms: the paracrine action of ocular purines and mechanical stretch of the trabecular meshwork. Three specific aims will be used to explore this hypothesis. In the first aim the Dr. Crosson's studies in purinergic regulation of aqueous humor dynamics will be extended to analysis of purinergic P2 agonists effects on intraocular pressure, aqueous flow and outflow facility. In the second specific aim the purinergic regulation of trabecular cell function will be evaluated. This will include studying purinergic modulation of MAP kinase pathways, cross talk between purinergic and other receptor systems and purinergic modulation of matrix metalloproteinase secretion and transcription. In the last specific aim the response of trabecular meshwork cells to stretch will be evaluated. The results from this work are predicted to 1) improve understanding of the physiological systems that regulate aqueous humor dynamics, 2) identify the signal transduction pathways that mediate purinergic and stretch-induced changes in trabecular meshwork cells and 3) develop a rational basis for the use of purinergic agonists in the treatment of glaucoma.